Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants

Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries

The chr12q24.13 locus encoding OAS1-OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-lambda 1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.N

Conditional regression results for 5′TNFSF4 variants in four groups.

<p>Conditional analyses in SNPTESTv2 Case Control. Continuous covariate within a clustering framework. P values selected using additional model and a frequentist paradigm.</p

SLE-associated <i>rs2205960</i> predicted to be part of a decameric motif for NF-κB p65 (RELA).

<p><i>A</i>. Degeneracy within the core 10-base motif is illustrated at all positions apart from position 7 which is non-degenerate by the stacked letters at each position. The relative height of each letter is proportional to its over-enrichment in the motif. A dashed line is boxed around <i>rs2205960-T</i>, this SLE-associated allele is predicted to form the 8^th nucleotide in the motif. Predictions were made using the non-degenerate set of matrix profiles in the Jaspar Core database. <i>B</i>. Altering the <i>rs2205960</i> allele from <i>-T</i> to <i>-G</i> decreases the binding affinity for NF-κB p65 by over 10%. <i>C</i>. Binding of NF-κB at <i>rs2205960</i>, suggested by genome-wide ChIP-seq ENCODE data. Profiles were generated for lymphoblatoid cell lines and stored in the UCSC genome database.</p

LD plots at <i>TNFSF4</i> locus in four populations.

<p>This section of chromosome 1q25.1 encompasses the <i>TNFSF4</i> gene and upstream region as defined by custom algorithm in Haploview 4.2. The measure of LD was used to depict 57 SNPs common to all cohorts, post QC and 1000 genomes imputation. The pair-wise correlations between <i>TNFSF4</i> markers is illustrated in these plots by the correlation coefficient R²(where r² = 0 = no correlation, white; 02<1, gradations of grey; R² = 1 = complete correlation, black). The <i>TNFSF4</i> gene is positioned above the plots relative to haplotype blocks (black triangles) and grey ticks indicate SNP locations to scale.</p

Haplotype Bifurcation Diagrams of <i>TNFSF4_risk</i> and <i>TNFSF4_non-</i>_<b>risk</b> for Four Populations.

<p>Plots are constructed using phased haplotypes for a. <i>East Asians</i>, b. <i>Europeans</i>, c. <i>Hispanics</i> and d. <i>African-Americans</i> and illustrate breakdown of LD with increasing distances from a core proximal <i>TNFSF4</i> SNP and are approximately to scale. The core is located at the <i>TNFSF4</i> gene-5′ boundary (black circle) and is selected as the most proximal 5′ marker, <i>rs1234314</i>, in each population. Gene location is depicted to scale; we have additionally labelled each plot to show the location of <i>rs1234317</i> and <i>rs2205960</i>, the best-associated markers from the meta-analysis.</p